Downregulate

Downregulate refers to processes that decrease the abundance or activity of a biological component in response to a stimulus. It can occur at multiple levels, including cell-surface receptors, gene expression, and protein stability. Receptor downregulation most commonly involves the reduction of receptor numbers at the plasma membrane following prolonged exposure to a ligand. This often occurs via endocytosis and targeting of receptors to lysosomes or proteasomes, diminishing cell responsiveness; such desensitization can be receptor-class specific, as with G protein-coupled receptors, or occur through broader signaling feedback loops.

Transcriptional downregulation decreases the production of messenger RNA for a given gene, reducing the synthesis of its protein. This can result from changes in transcription factor activity, promoter methylation, histone modification, or noncoding RNA interaction. Post-translational downregulation increases the removal or degradation of existing proteins, for example through ubiquitination and proteasomal or lysosomal pathways.

Researchers use several approaches to study downregulation, including RNA interference (siRNA, shRNA) to lower mRNA levels, antisense oligonucleotides, and CRISPR interference to suppress transcription. Pharmacological agents may also cause downregulation by sustained activation or inhibition of signaling pathways.

Biological significance varies: downregulation can prevent overactivation and maintain homeostasis, but it can also contribute to drug tolerance, altered sensitivity in disease states, or compensatory changes within signaling networks. Examples include beta-adrenergic receptor downregulation after chronic agonist exposure and insulin receptor regulation in metabolic conditions.

See also upregulation and desensitization.